Metformin Affects Cardiac Arachidonic Acid Metabolism and Cardiac Lipid Metabolite Storage in a Prediabetic Rat Model

Metformin can reduce cardiovascular risk independent of glycemic control. The mechanisms behind its non-glycemic benefits, which include decreased energy intake, lower blood pressure and improved lipid and fatty acid metabolism, are not fully understood. In our study, metformin treatment reduced myocardial accumulation of neutral lipids—triglycerides, cholesteryl esters and the lipotoxic intermediates—diacylglycerols and lysophosphatidylcholines in a prediabetic rat model (p < 0.001). We observed an association between decreased gene expression and SCD-1 activity (p < 0.05). In addition, metformin markedly improved phospholipid fatty acid composition in the myocardium, represented by decreased SFA profiles and increased n3-PUFA profiles. Known for its cardioprotective and anti-inflammatory properties, metformin also had positive effects on arachidonic acid metabolism and CYP-derived arachidonic acid metabolites. We also found an association between increased gene expression of the cardiac isoform CYP2c with increased 14,15-EET (p < 0.05) and markedly reduced 20-HETE (p < 0.001) in the myocardium. Based on these results, we conclude that metformin treatment reduces the lipogenic enzyme SCD-1 and the accumulation of the lipotoxic intermediates diacylglycerols and lysophosphatidylcholine. Increased CYP2c gene expression and beneficial effects on CYP-derived arachidonic acid metabolites in the myocardium can also be involved in cardioprotective effect of metformin.

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Phospholipid Fatty Acid Composition and Arachidonic Acid Metabolism in Selected Tissues of Adult Tenebrio molitor (Coleoptera: Tenebrionidae)

Annals of the Entomological Society of America ◽

10.1093/aesa/83.5.975 ◽

1990 ◽

Vol 83 (5) ◽

pp. 975-981 ◽

Cited By ~ 32

Author(s):

Ralph W. Howard ◽

David W. Stanley-Samuelson

Keyword(s):

Arachidonic Acid ◽

Fatty Acid Composition ◽

Fatty Acid ◽

Acid Composition ◽

Acid Metabolism ◽

Phospholipid Fatty Acid ◽

Tenebrio Molitor ◽

Arachidonic Acid Metabolism ◽

Phospholipid Fatty Acid Composition ◽

Coleoptera Tenebrionidae

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Regulation of arachidonic acid metabolism by cytochrome P-450 in rabbit kidney

Biochemical Journal ◽

10.1042/bj2380283 ◽

1986 ◽

Vol 238 (1) ◽

pp. 283-290 ◽

Cited By ~ 63

Author(s):

M L Schwartzman ◽

N G Abraham ◽

M A Carroll ◽

R D Levere ◽

J C McGiff

Keyword(s):

Arachidonic Acid ◽

Acid Metabolism ◽

Arachidonic Acid Metabolism ◽

Rabbit Kidney ◽

Aryl Hydrocarbon Hydroxylase ◽

Outer Medulla ◽

Aryl Hydrocarbon ◽

Arachidonic Acid Metabolites ◽

Acid Metabolites ◽

Cytochrome P 450

Renal microsomal cytochrome P-450-dependent arachidonic acid metabolism was correlated with the level of cytochrome P-450 in the rabbit kidney. Cobalt, an inducer of haem oxygenase, reduced cytochrome P-450 in both the cortex and medulla in association with a 2-fold decrease in aryl-hydrocarbon hydroxylase, an index of cytochrome P-450 activity, and a similar decrease in the formation of cytochrome P-450-dependent arachidonic acid metabolites by renal microsomes (microsomal fractions). Formation of the latter was absolutely dependent on NADPH addition and was prevented by SKF-525A, an inhibitor of cytochrome P-450-dependent enzymes. Arachidonate metabolites of cortical microsomes were identified by g.c.-m.s. as 20- and 19-hydroxyeicosatetraenoic acid, 11,12-epoxyeicosatrienoic acid and 11,12-dihydroxyeicosatrienoic acid. The profile of arachidonic acid metabolites was the same for the medullary microsomes. Induction of cytochrome P-450 by 3-methylcholanthrene and beta-naphthoflavone increased cytochrome P-450 content and aryl-hydrocarbon hydroxylase activity by 2-fold in the cortex and medulla, and this correlated with a 2-fold increase in arachidonic acid metabolites via the cytochrome P-450 pathway. These changes can also be demonstrated in cells isolated from the medullary segment of the thick ascending limb of the loop of Henle, which previously have been shown to metabolize arachidonic acid specifically via the cytochrome P-450-dependent pathway. The specific activity for the formation of arachidonic acid metabolites by this pathway is higher in the kidney than in the liver, the highest activity being in the outer medulla, namely 7.9 microgram as against 2.5 micrograms of arachidonic acid transformed/30 min per nmol of cytochrome P-450 for microsomes obtained from outer medulla and liver respectively. These findings are consistent with high levels of cytochrome P-450 isoenzyme(s), specific for arachidonic acid metabolism, primarily localized in the outer medulla.

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THE VARIATION OF ARACHIDONIC ACID METABOLISM OF PMN LEUKOCYTES IN CEREBRAL THROMBOSIS

10.1055/s-0038-1643155 ◽

1987 ◽

Author(s):

Z Wang ◽

B Lehuu ◽

Y He ◽

C Raun

Keyword(s):

Arachidonic Acid ◽

Acid Metabolism ◽

Arachidonic Acid Metabolism ◽

Cerebral Thrombosis ◽

Potent Inducer ◽

Tissue Ischemia ◽

Significant Difference ◽

Arachidonic Acid Metabolites ◽

Pmn Leukocytes ◽

Acid Metabolites

It was suggested that there is a transfer of metabolites between leukocytes,paltelets and endothelial cells,and that the leukocytes might take part in thrombosis and haemostasis. In order to ascertain whether the arachidonic acid metabolism of PMN leukocytes changes when cerebral thrombosis occurs, we studied this metabolism using isolated human PMN leukocytes, stimulated by ionophor A23187. PGE2 and TXB2 were measured with the method of radioimmunoassay, while leukotrienes(LT) were separated and measured by HPLC. The amount of PGE2, TXB2 and LTs produced by PMN leukocytes of 8 normal volunteers was compared with that of 8 patients suffering from cerebral thrombosis. All these patients were confirmed by CT examination. We found that the production of TXB2, LTB4 and its derivative 20-0H-LTB4 of PMN leukocytes of patients was significantly enhanced. The PGE2 production of PMN leukocytes of patients was also higher than that 0? the volunteers, but without statistically significant difference.These results demonstrate that leukocytes and their arachi donic acid metabolites might play some role in the pathogenetic sequence of cerebral thrombosis. And it is possible that LTB4 is not only a potent inducer of neutrophil chemotaxis and leukocyte aggregation, but also an associated factor in the ischemic vascular disease. It seems that the increasing production of TXB2 and LTB4 by PMN leukocytes is not the main reason of cerebral thrombosis. Hoever, it might accelerate the degree of brain tissue ischemia. We observed that corticosteroids, as an inhibitor of phosphoIipase A2,strikingly reduced the production of arachidonic acid metabolites by leukocytes. Therefore, it is probable that the efficacy of corticosteroids on cerebral thrombosis is, in part, due to inhibit the production of these arachidonic acid metabolites of leukocytes.

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Inhibition of phorbol ester-induced monocytic differentiation and c-fms gene expression by dexamethasone: potential involvement of arachidonic acid metabolites

Blood ◽

10.1182/blood.v76.6.1225.1225 ◽

1990 ◽

Vol 76 (6) ◽

pp. 1225-1232 ◽

Cited By ~ 32

Author(s):

RM Stone ◽

K Imamura ◽

R Datta ◽

ML Sherman ◽

DW Kufe

Keyword(s):

Gene Expression ◽

Arachidonic Acid ◽

Arachidonic Acid Metabolism ◽

Detectable Effect ◽

Mrna Levels ◽

Monocytic Differentiation ◽

Arachidonic Acid Metabolites ◽

Acetate Esterase ◽

Acid Metabolites ◽

Acid Pathway

Abstract The treatment of human U-937 leukemia cells with 12-O- tetradecanoylphorbol-13-acetate (TPA) is associated with induction of monocytic differentiation. However, the signaling pathways responsible for induction of the differentiated monocytic phenotype remain unclear. The present studies demonstrate that dexamethasone blocks TPA-induced U- 937 cell growth inhibition, adherence, and alpha-naphthyl acetate esterase staining. The results also demonstrate that dexamethasone inhibits the appearance of c-fms transcripts associated with TPA treatment. Run-on transcription assays demonstrated that the c-fms gene is transcriptionally active in uninduced U-937 cells and that the rate of transcription is unchanged after dexamethasone and/or TPA treatment. These findings indicated that TPA increases c-fms expression by a dexamethasone-sensitive posttranscriptional mechanism. Treatment of U- 937 cells with TPA was also associated with stimulation of arachidonic acid metabolism. Furthermore, dexamethasone, an inhibitor of phospholipase A2 activity, blocked TPA-induced increases in arachidonic acid release. These findings suggested that TPA may regulate certain features of monocytic differentiation, such as c-fms gene expression, through the formation of arachidonic acid metabolites. Indomethacin, an inhibitor of cyclooxygenase, had no detectable effect on c-fms gene expression. However, the cyclooxygenase metabolite, prostaglandin E2, inhibited the TPA-induced increases in c-fms mRNA levels. Taken together, the results indicate that TPA regulates c-fms gene expression by a dexamethasone-sensitive mechanism and that c-fms mRNA levels are controlled by metabolites of the arachidonic acid pathway.

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Inhibition of phorbol ester-induced monocytic differentiation and c-fms gene expression by dexamethasone: potential involvement of arachidonic acid metabolites

Blood ◽

10.1182/blood.v76.6.1225.bloodjournal7661225 ◽

1990 ◽

Vol 76 (6) ◽

pp. 1225-1232 ◽

Cited By ~ 1

Author(s):

RM Stone ◽

K Imamura ◽

R Datta ◽

ML Sherman ◽

DW Kufe

Keyword(s):

Gene Expression ◽

Arachidonic Acid ◽

Arachidonic Acid Metabolism ◽

Detectable Effect ◽

Mrna Levels ◽

Monocytic Differentiation ◽

Arachidonic Acid Metabolites ◽

Acetate Esterase ◽

Acid Metabolites ◽

Acid Pathway

The treatment of human U-937 leukemia cells with 12-O- tetradecanoylphorbol-13-acetate (TPA) is associated with induction of monocytic differentiation. However, the signaling pathways responsible for induction of the differentiated monocytic phenotype remain unclear. The present studies demonstrate that dexamethasone blocks TPA-induced U- 937 cell growth inhibition, adherence, and alpha-naphthyl acetate esterase staining. The results also demonstrate that dexamethasone inhibits the appearance of c-fms transcripts associated with TPA treatment. Run-on transcription assays demonstrated that the c-fms gene is transcriptionally active in uninduced U-937 cells and that the rate of transcription is unchanged after dexamethasone and/or TPA treatment. These findings indicated that TPA increases c-fms expression by a dexamethasone-sensitive posttranscriptional mechanism. Treatment of U- 937 cells with TPA was also associated with stimulation of arachidonic acid metabolism. Furthermore, dexamethasone, an inhibitor of phospholipase A2 activity, blocked TPA-induced increases in arachidonic acid release. These findings suggested that TPA may regulate certain features of monocytic differentiation, such as c-fms gene expression, through the formation of arachidonic acid metabolites. Indomethacin, an inhibitor of cyclooxygenase, had no detectable effect on c-fms gene expression. However, the cyclooxygenase metabolite, prostaglandin E2, inhibited the TPA-induced increases in c-fms mRNA levels. Taken together, the results indicate that TPA regulates c-fms gene expression by a dexamethasone-sensitive mechanism and that c-fms mRNA levels are controlled by metabolites of the arachidonic acid pathway.

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